In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an ∼30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.

在囊性纤维化 (CF) 中，过量弗林蛋白酶活性在上皮钠通道 (ENaC) 的激活中起关键作用，其失调会导致气道脱水、无效的粘液纤毛清除 (MCC) 和粘液阻塞。在这里，我们报告了一种高选择性、细胞渗透性弗林蛋白酶抑制剂 BOS-318，它通过引发一个新的、意想不到的结合口袋的形成来获得选择性，该口袋独立于活性位点催化三联体。使用人类离体在模型中，BOS-318 显示出对 ENaC 的显着抑制，这导致气道水合作用增强和 MCC 率增加约 30 倍。弗林蛋白酶抑制还保护 ENaC 免受中性粒细胞弹性蛋白酶的后续激活，中性粒细胞弹性蛋白酶是一种在 CF 气道中占主导地位的可溶性蛋白酶。其他治疗益处包括防止铜绿假单胞菌外毒素 A 诱导的上皮细胞死亡。我们的研究结果证明了选择性弗林蛋白酶抑制剂作为一种突变不可知方法的效用，可以以预期提供治疗价值的方式纠正 CF 气道病理生理学的特征。